Discovery, synthesis and biological characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators

Swagat Sharma; Lauren Lesiak; Christopher D. Aretz; Yu Du; Sushil Kumar; Nagsen Gautam; Yazen Alnouti; Nikilesh V. Dhuria; Yashpal S. Chhonker; C. David Weaver; Corey R. Hopkins

doi:10.1039/D1MD00129A

Discovery, synthesis and biological characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators†

Swagat Sharma,^a Lauren Lesiak,^a Christopher D. Aretz,^a Yu Du,^b Sushil Kumar,^a Nagsen Gautam,^a Yazen Alnouti,^a Nikilesh V. Dhuria,^c Yashpal S. Chhonker,^c C. David Weaver

^b and Corey R. Hopkins

*^a

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* Corresponding authors

^a Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198 USA
E-mail: corey.hopkins@unmc.edu

^b Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA

^c Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198 USA

Abstract

The present study describes the discovery and characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as G protein-gated inwardly-rectifying potassium (GIRK) channel activators. From our previous lead optimization efforts, we have identified a new ether-based scaffold and paired this with a novel sulfone-based head group to identify a potent and selective GIRK1/2 activator. In addition, we evaluated the compounds in tier 1 DMPK assays and have identified compounds that display nanomolar potency as GIRK1/2 activators with improved metabolic stability over the prototypical urea-based compounds.

This article is part of the themed collection: Chemical Probes

RSC Medicinal Chemistry

Discovery, synthesis and biological characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators†

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Discovery, synthesis and biological characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators

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